PROJECT SUMMARY Accumulating evidence supports the involvement of memory consolidation and dendritic spine abnormalities in psychiatric disorders. There is currently a critical need for identifying the morphological correlates of memory consolidation, and linking these correlates to emotional memories acquired during recent learning to improve our understanding of memory consolidation and develop effective therapeutic strategies. We focus on the two interconnected regions critically involved in fear memory and implicated in schizophrenia and post-traumatic stress disorder, the hippocampus and the amygdala. Our preliminary data showing higher numbers of dendritic spines in the hippocampus of sleep deprived mice supports the theory of broad synaptic downscaling during sleep, and contradicts a recent report that sleep deprivation results in decreased hippocampal dendritic spines. These differences may arise from limitations of the methodological approaches used in published studies, and in the inability to link specific neurons to recently learned memory traces. The proposed investigations will use a combination of viral vector neuronal labeling and transgenic mice to allow for quantification of dendritic spines in neurons involved in recent fear learning in comparison to neurons not involved in acquiring the recent fear memory. This approach will allow us to test the hypothesis that dendritic spines are strengthened during sleep in neurons involved in recent fear learning while other neurons in the same brain regions undergo broad synaptic downscaling. Specific Aim 1 will test the hypothesis that sleep deprivation prevents broad synaptic downscaling in the hippocampus and amygdala. Specific Aim 2 will test the hypothesis that dendritic spines formed during recent fear learning are reduced by sleep deprivation. The proposed studies represent a first step toward broader investigations into the morphological and molecular changes associated with memory consolidation dysfunction in schizophrenia and post-traumatic stress disorder, and will allow for critical information that may link the theory of synaptic homeostasis of sleep with recent evidence that dendritic spines in certain brain regions may be strengthened during sleep.